Although the process of restenosis after percutaneous transluminal coronary angioplasty (PTCA) is complex and not fully understood, vascular smooth muscle cell (VSMC) migration and proliferation are critical underlying events. Recent studies within our lab in rat cultured VSMCs have shown tha one important mechanism underlying restenosis involves the expression and activation of matrix metalloproteinases (MMPs). Data from this project shows that in vivo, the production of MMP-2 increases following vascular injury and is preferentially distributed in the newly forming neointimal cells of the restenotic lesion. The functional significance of the MMPs i presently being assessed in an ongoing trial in the pig model in which animals are being treated with a MMP peptide inhibitor following balloon injury of the coronary arteries. Following vascular injury a number of growth factors and cytokines stimulate VSMC migration and proliferation. Studies within our group have focused on understanding signal transduction pathways mediated by these factors involving inositol phospholipid -specifi phospholipase C (PLC). Preliminary results suggest the PLC-~1 and PLC-k1 but not PLC-beta1 are amplified following vascular injury implying that these isoforms of PLC may play a important role in neointima formation following arterial injury. Effective strategies to inhibit PLC activation are being investigated. The application of effective therapeutic strategie to the treatment of restenosis in animals and humans is heavily dependent o the development of intravascular site-specific delivery mechanisms. In collaboration with the gene therapy unit of our laboratory we are using the replication deficient recombinant adenovirus as a delivery vehicle to asses the functional significance of specific genes on restenosis in the rat and pig. In addition, we have developed sustained-release biodegradable microcapsules via which therapeutic agents can be delivered to the vessel wall Recently, we have demonstrated that Taxol, a potent anti-cancer drug, administered by this mitral inhibits VSMC migration and proliferation. Additional studies are underway in the pig restenosis model using Taxol impregnated within microcapsules delivered intravascularly. The challenge and hope of our studies are that these therapies developed within the constraints of available animal models will translate into patient benefit in clinical trials of restenosis after PTCA.